Substance P(SP) is a neuropeptide for which transmitter and/or neuromodulator roles have been postulated. Pharmacologically, SP elicits numerous physiological and behavioral effects, such as smooth muscle contraction, vasodilation, analgesia, and alterations in learning and aggression. The mechanism(s) of action of SP, and the intrinsic biological functions to which these effects are presumably related, are unknown. SP is known to interact with monoamine neurotransmitters, specifically dopamine and serotonin, through which its actions may be expressed. Almost nothing is known about the biosynthesis or degradation of SP, or about the receptor(s) through which it acts, especially in the CNS. Lack of specific SP antagonists has hampered studies of the effects of SP. One of the few tools available for studies of SP function is synthetic structural analogs of SP. Such analogs and fragments have shown that SP receptors in the periphry on smooth muscle such as intestine and arterioles respond only to the C-terminal part of the SP molecule. We have found that some CNS effects of SP can be elucidated by the N-terminaal region of the SP molecule, a region apparently devoid of activity in the periphery. Analogs of SP will be synthesized and tested on several complex CNS functions to determine the structural requirements for eliciting SP effects on these functions and to develop potent and long-lasting agonists. Specific antagonists of N- and C-terminal activities will be sought. These peptides may lead to development of drugs for treatment of CNS disorders involving dopamine or serotonin malfunction.